title: Peptides based on CcdB protein as novel inhibitors of bacterial topoisomerases.
abstract: The ccd toxin-antitoxin system of the F plasmid encodes CcdB, a protein that poisons the essential Escherichia coli DNA gyrase, unique type IIA topoisomerase able to introduce negative supercoils into DNA. Based on CcdB structure, a series of linear peptide analogues were obtained by the solid-phase methodology. One of these peptides (CcdBET2) displayed inhibition of the supercoiling activity of bacterial DNA gyrase with a concentration required for complete inhibition (IC(100)=10 microM) lower than the wild type CcdB. For Topo IV, a second type IIA bacterial topoisomerase, CcdBET2 was better inhibited the relaxation activity with an IC(100) of 5 microM (wt CcdB>10 microM). The replacement of Gly, present in the three C-terminal amino acid residues, by Glu, abolished the capacity to inhibit the gyrase but not the Topo IV activities. These findings demonstrate that the mechanism by which CcdBET2 inhibits DNA gyrase is different of the mechanism by which inhibits Topo IV. Therefore, CcdBET2 is a new type II topoisomerase inhibitor with specificity for Topo IV.
authors.affiliation: UNESP-Institute of Chemistry, Department of Biochemistry and Technological Chemistry, Caixa Postal 355, 14800-900 Araraquara, SP, Brazil.
authors.forename: Eliane
authors.initials: E
authors.lastname: Trovatti
authors.forename: Camila A
authors.initials: CA
authors.lastname: Cotrim
authors.forename: Saulo S
authors.initials: SS
authors.lastname: Garrido
authors.forename: Ronaldo S
authors.initials: RS
authors.lastname: Barros
authors.forename: Reinaldo
authors.initials: R
authors.lastname: Marchetto
mesh_terms: D000596:Amino Acids / Q000235:genetics; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D001427:Bacterial Toxins / Q000235:genetics / Q000378:metabolism*; D027101:DNA Topoisomerase IV / Q000235:genetics / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000235:genetics; D004926:Escherichia coli / Q000201:enzymology; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides / Q000138:chemical synthesis* / Q000494:pharmacology; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
chemical_list: D000596:Amino Acids; D001426:Bacterial Proteins; D001427:Bacterial Toxins; C068356:CcdB protein, Plasmid F; C534186:CcdBET2; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D059005:Topoisomerase II Inhibitors; D027101:DNA Topoisomerase IV; D004250:DNA Topoisomerases, Type II